Since the discovery of erythromycin A (ERY), macrolide antibiotics (macrolides) have been an important class of molecules for treating a wide variety of bacterial infections. Further, research on macrolides has provided the discovery of several new generations of macrolide antibiotics. One group is the clarithromycin (CLR) class of compounds, where the ring structure was stabilized by the methylation of the C-6 hydroxyl. Another group is the 15-membered ring aza analogs, of which azithromycin (AZI) is a notorious member. Another groups is the 3-desglycosyl-3-oxo analogs, also known as ketolides, of which telithromycin (TEL) and cethromycin (CTH) are notorious members. However, as has been true for other antibiotic classes of molecules, such as the penecillins, cephalosporins, quinolones, vancomycin, and others, resistant organisms have emerged throughout the world. Macrolide resistance, which is now predominant in some countries such as Japan and Korea, has been blamed on the overuse of AZI and CLR during the past 15 years. It has also been observed that macrolide resistance also usually occurs together with penicillin G resistance (though genetically unlinked). For example, though all strains of group A streptococci are still β-lactam susceptible, macrolide resistance has occurred, especially in Asia and in southern, central and eastern Europe. Infections caused by drug-resistant group A streptococci are encountered worldwide and sometimes life-threatening infections caused by these organisms are encountered. Further, Streptococcus pyogenes strains, although retaining their β-lactam susceptibility are becoming more macrolide resistant. It is estimated that nearly 40% of Streptococcus strains in the US are resistant to both penicillin and macrolide antibiotics.
In fact, it has been suggested that the introduction of TEL into the therapeutic armamentarium was intended to solve the problem of macrolide resistance in streptococci. TEL is effective against penicillin and erythromycin-resistant S. pneumoniae and is a non-inducer of Macrolide-Lincosamide-Streptogramin B (MLSB) resistance. However, even with TEL, which is active against many macrolide resistant S. pyogenes genotypes, resistant species have and continue to emerge. In particular, ketolide resistant species, namely to TEL, but also possibly cross resistant with CTH, have been reported worldwide, and most recently in S. pyogenes from Europe. Further, TEL is not active against erm(B) group A streptococci (which are naturally TEL resistant). Moreover, observed TEL toxicities have limited the clinical utility of this drug. The rapid emergence of resistant strains may not be surprising; when the free AUC/MIC of TEL against macrolide-resistant pneumococci even with low MICs is examined carefully, it is observed that the number was not significantly above 25. Thus, the high probability of resistance developing might be predicted to occur.
In addition, though the pediatric conjugate vaccine has dramatically decreased meningitis and bacteremia caused by most of the usual drug-resistant pneumococcal clones, outbreaks of serious cases of otitis media caused by pan-resistant strains with a serotype (19A) not included in the vaccine have been reported. Thus, the problem of drug-resistant pneumococci causing community-acquired respiratory infection, especially in children, is likely to worsen with the spread of this clone.
Several specific macrolide resistant mechanisms have been reported, including ribosomal methylation-based resistance (erm(A), erm(B)), efflux-based resistance (mef(A), mef(E), mef(I)), and resistance arising from mutation of the rRNA or ribosomal protein, such as 23S and L4 mutations.
Accordingly, a continuing need for new antibiotics and anti-bacterial agents remains. Further, those new agents would desirably have the property of a low potential for resistance development or induction, and a low potential for naturally occurring resistance.
It has been surprisingly discovered herein that triazole-containing macrolides, including ketolides, exhibit high activity in vitro and in vivo against numerous organisms. Moreover, it has been discovered that the triazole-containing macrolides described herein exhibit high activity in vitro and in vivo against numerous resistant organisms, including both macrolide and ketolide resistant organisms.
In one illustrative embodiment, compounds of Formula (I) are described herein
including pharmaceutically acceptable salts, hydrates, solvates, esters, and prodrugs thereof.
In one aspect, R10 is hydrogen or acyl. In another aspect, X is H; and Y is OR7; where R7 is a monosaccharide or disaccharide, alkyl, aryl, heteroaryl, acyl, or C(O)NR8R9, where R8 and R9 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, heteroalkyl, aryl, heteroaryl, alkoxy, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; or X and Y are taken together with the attached carbon to form carbonyl.
In another aspect, V is C(O), C(═NR11), CH(NR12, R13), or N(R14)CH2, where N(R14) is attached to the C-10 carbon of the compounds of Formulae 1 and 2; wherein R11 is hydroxy or alkoxy, R12 and R13 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; R14 is hydrogen, hydroxy, alkyl, aralkyl, alkylaryl, alkoxy, heteroalkyl, aryl, heteroaryl, dimethylaminoalkyl, acyl, sulfonyl, ureido, or carbamoyl.
In another aspect, W is H, F, Cl, Br, I, or OH.
In another aspect, A is CH2, C(O), C(O)O, C(O)NH, S(O)2, S(O)2NH, C(O)NHS(O)2. In another aspect, B is (CH2)n where n is an integer ranging from 0-10, or B is an unsaturated carbon chain of 2-10 carbons. In another aspect, C is hydrogen, hydroxy, alkyl, aralkyl, alkyl aryl, alkoxy, heteroalkyl, aryl, heteroaryl, aminoaryl, alkylaminoaryl, acyl, acyloxy, sulfonyl, ureido, or carbamoyl.
In another embodiment, compositions including a therapeutically effective amount of one or more compounds of formula (I), or the various subgenera thereof are described herein. The pharmaceutical compositions may include additional pharmaceutically acceptable carriers, diluents, and/or excipients.
In another embodiment, methods are described herein for treating diseases arising from pathogenic organism populations. The methods include the step of administering a therapeutically effective amount of one or more compounds of formula (I), or the various subgenera thereof are described herein, to a patient in need of relief or suffering from a disease caused by a pathogenic organism.
In another embodiment, uses are described herein for the manufacture of medicaments. The medicaments include a therapeutically effective amount of one or more compounds of formula (I), or the various subgenera thereof are described herein, or one or more compositions thereof described herein. The medicaments are suitable for treating diseases arising from pathogenic organism populations.